Since the discovery that keratinocyte derived "Epidermal thymocyte activating factor" was molecularly identical to interleukin 1 (IL-1), this molecular has been implicated in a number of pathophysiological processes relevant to skin disease. While interesting, it has been difficult to rigorously test such hypotheses in parallel, it has become clear that IL-1 is one of the most extensively regulated cytokine systems in all of biology. Two genes encode for two IL-1 receptors. The IL-1R (T1) is the sole signal transducing receptor for IL-1. The IL-1. The IL-1R (T2) binds IL-1 agonists (not antagonists), but does not transduce a signal. IL-1R2 is readily shed from cells and scavenges IL-1. Keratinocytes express both types of IL-1R. Two distinct genes encode for two agonist moleculs, IL- 1alpha and beta, the latter of which must be proteolytically processed by interleukin 1beta converting enzyme (ICE) to become active. Monocytes, but not keratinocytes, express ICE. Another gene encodes for two alternatively spliced forms of a pure antagonist of the IL-1R1, called secreted (s)IL-1 receptor antagonist (ra) and intracellular (ic) IL-1 ra. Both bind avidly to the IL-1R1, but poorly to the IL-1R2. Published reports have found aberrant levels of at least one of these IL-1 axis molecules in several skin diseases, including psoriasis vulgaris, cutaneous T cell lymphoma, contract hypersensitivity, acne vulgaris, and tumor promoter-induced inflammation. While useful, such associations of Il-1 axis member and disease state do not address issues of cause, effect, and epiphenomenon. The hypothesis to be tested in the present proposal is that the balance of agonists (IL-1R1), active IL-1) and antagonists (IL-1R2,IL-1ra) in the cutaneous microenvironment dictates the outcome of autocrine and paracrine IL-1 inducible events in skin. We have created transgenic mice whose basal epidermal keratinocytes overexpress, respectively, IL-1alpha, IL-1R1, sIL-1ra, and IL-1R2. In preliminary experiments, we have shown that relevant cutaneous pathophysiological processes are significantly altered in these transgenic mice exhibiting an imbalance of agonists or antagonists of Il-1 activity. These mice will be used to study three processes where substantial circumstantial evidence implicates the IL-1 axis in disease pathogenesis: contact hypersensitivity, graft versus host disease (and allograft rejection), and chemical epidermal carcinogenesis. We believe that analysis of these unique transgenic mice will permit a more precise definition of the role of the IL-1 axis in vivo in these clinically relevant murine models of skin disease.